rs1042820

Variant names:

• chr2-47783419-C-A
• rs1042820
• NM_000179.3:c.186C>A
• MSH6 p.Arg62Arg

Your query was ambiguous. Multiple possible variants found:

• chr2-47783419-C-A
• chr2-47783419-C-G
• chr2-47783419-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001406804.1(MSH6):​c.131C>A​(p.Ala44Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,511,208 control chromosomes in the GnomAD database, including 22,660 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A44T) has been classified as Likely benign. The gene MSH6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.13 (1544 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21116 hom.)
• Consequence: MSH6 NM_001406804.1 missense
• Clinical Significance: Benign reviewed by expert panel B:23
• Conservation: PhyloP100: -0.0560
• Publications: 29 publications found

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

MSH6 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
• Lynch syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 2-47783419-C-A is Benign according to our data. Variant chr2-47783419-C-A is described in ClinVar as Benign. ClinVar VariationId is 36584.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406804.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.186C>A	p.Arg62Arg	synonymous	Exon 1 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406804.1		c.131C>A	p.Ala44Asp	missense	Exon 1 of 10	NP_001393733.1
	MSH6	NM_001406795.1		c.186C>A	p.Arg62Arg	synonymous	Exon 1 of 11	NP_001393724.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.186C>A	p.Arg62Arg	synonymous	Exon 1 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.186C>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.186C>A	p.Arg62Arg	synonymous	Exon 1 of 10	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19171 AN: 152048 Hom.: 1546 Cov.: 32

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.000971

Gnomad SAS AF: 0.0596

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.144 AC: 16491 AN: 114188 AF XY: 0.146

Gnomad AFR exome AF: 0.0571

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.000400

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.170 AC: 231000 AN: 1359046 Hom.: 21116 Cov.: 34 AF XY: 0.167 AC XY: 112006 AN XY: 668872

African (AFR) AF: 0.0439 AC: 1242 AN: 28280

American (AMR) AF: 0.0978 AC: 2691 AN: 27522

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 3782 AN: 22638

East Asian (EAS) AF: 0.000413 AC: 14 AN: 33924

South Asian (SAS) AF: 0.0772 AC: 5763 AN: 74690

European-Finnish (FIN) AF: 0.121 AC: 5706 AN: 47062

Middle Eastern (MID) AF: 0.165 AC: 902 AN: 5466

European-Non Finnish (NFE) AF: 0.190 AC: 202332 AN: 1063586

Other (OTH) AF: 0.153 AC: 8568 AN: 55878

GnomAD4 genome AF: 0.126 AC: 19169 AN: 152162 Hom.: 1544 Cov.: 32 AF XY: 0.122 AC XY: 9103 AN XY: 74406

African (AFR) AF: 0.0531 AC: 2205 AN: 41552

American (AMR) AF: 0.123 AC: 1886 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 532 AN: 3472

East Asian (EAS) AF: 0.000974 AC: 5 AN: 5134

South Asian (SAS) AF: 0.0597 AC: 288 AN: 4828

European-Finnish (FIN) AF: 0.121 AC: 1285 AN: 10614

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.184 AC: 12477 AN: 67944

Other (OTH) AF: 0.142 AC: 300 AN: 2114

Alfa AF: 0.107 Hom.: 303

Bravo AF: 0.126

Asia WGS AF: 0.0410 AC: 143 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	Lynch syndrome 5 (3)
-	-	3	not provided (3)
-	-	2	Lynch syndrome (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.7
DANN	Benign	0.80
PhyloP100		-0.056
PromoterAI		0.086	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1042820;

hg19: chr2-48010558;

COSMIC: COSV52276343;

COSMIC: COSV52276343;